The term proteinuria derives from protein and urine and means the presence of an excess of serum proteins in the urine. Proteinuria may be a sign of renal (kidney) damage, since serum proteins are readily reabsorbed from urine, the presence of excess protein indicates either an insufficiency of absorption or impaired filtration. Proteinuria may be a feature of the following conditions: Nephrotic syndromes (i.e. intrinsic renal failure); toxic lesions of kidneys; Collagen vascular diseases (e.g., systemic lupus erythematosus); Glomerular diseases, such as membranous glomerulonephritis, focal segmental glomerulonephritis; Strenuous exercise; Stress; Diabetes mellitus; Drugs (e.g., NSAIDs, nicotine, penicillamine, gold and other heavy metals, ACE inhibitors, antibiotics, opiates especially heroin); Infections (e.g., HIV, syphilis, hepatitis, post-streptococcal infection); Aminoaciduria; Hypertensive nephrosclerosis; Interstitial nephritis and Glomerulosclerosis.
Glomerulosclerosis is a general term to describe scarring of the kidneys' tiny blood vessels, the glomeruli, the functional units in the kidney that filter urine from the blood. Many patients with glomerulosclerosis gradually get worse until their kidneys fail completely. This condition is called end-stage renal disease or ESRD. Patients with ESRD must go on dialysis (hemodialysis or peritoneal dialysis) to clean their blood or get a new kidney through transplantation.
The kidney glomerulus is a highly specialized structure that controls the plasma ultrafiltration of proteins. The specific cellular unit that ensures this control is the podocyte whose dysfunction is involved in a massive loss of proteins in the urine (proteinuria). It is well known that podocyte function is strictly under the control of specific proteins modulating the actin cytoskeleton. Mutations into the genes coding for such podocyte proteins are known to be associated with alterations of the glomerular membrane barrier and consequently with massive proteinuria and renal damage. Among these podocyte proteins, nephrin is a fundamental constituent of the slit pore membrane and modulates the cytoskeleton dynamics through the activation of a signal transduction pathway mediated by the tyrosin kinase Fyn which belongs to the Src family kinases (Trends Mol Med. 2007; 13: 396-403).
Adducin is a cytoskeletal protein involved in the regulation of the actin-spectrin dynamics in all the cells. Polymorphisms of the adducin genes have been demonstrated to be associated with hypertension and progression of the renal failure.
Experimental data indicate that α and β adducin are expressed into the glomerulus and their polymorphisms are involved in the altered expression of some podocyte proteins, proteinuria and progression of renal damage in animal models independently from their blood pressure. (J Hypertension 2003, 21 (Suppl. 4), abs 4C.4).
In details, the knockout mice for mutant β adducin, which are normotensive, show an increased expression of podocyte proteins, such as nephrin, synaptopodin, α-actinin, Fyn and ZO-1 and a reduction of urinary protein (FIG. 1), as compared with control mice, indicating a possible role of β adducin in the modulation of glomerular permeability independent from the blood pressure control.
In normotensive congenic NB rats, where the mutant β adducin gene from the parental hypertensive MHS strain (Q529R) has been introgressed into the normotensive MNS background (BBRC 2004; 324: 562-568), the expression of some podocyte proteins (nephrin, α-actinin, podocyn and ZO-1) measured in cultured podocytes have been found reduced (see FIG. 2) and associated to massive proteinuria and renal damage, as indicated by the immunofluorescence data (see FIG. 3) of the adult rats, as compared with the normotensive congenic NA strain carrying the wild type β adducin variant together with the α mutated one from the MHS strain. These findings are therefore suggestive of a pathological role of the mutant β adducin on kidney function, which is independent from blood pressure and is modulated by the α mutant variant.
The relevance of the experimental data obtained in the animal models for the human disease is supported by recent clinical findings showing that patients with IgA nephropathy have a faster progression toward end stage renal failure when carrying the β adducin mutation (CT+TT) in interaction with the α adducin mutated variant (Trp) (see FIG. 4).
Endogenous Ouabain (EO) has been widely recognized as a new hormone able to control blood pressure through different mechanisms and mainly through the modulation of the renal Na handling. High circulating levels of EO have been found associated with high blood pressure.
17-(3-Furyl) and (4-pyridaziny)-5-β, 14-β-androstane derivative are known compound.
EP0583578B 1 describes the beta-androstane derivatives claimed in the present application, a process for their preparation and their use for the treatment of cardiovascular disorders such as heart failure and hypertension.
EP0590271B 1 describes 17-aryl and 17-heterocyclyl-S-alpha, 14-β-androstane, androstene and androstadiene derivatives, a process for their preparation and their use for the treatment of cardiovascular disorders such as heart failure and hypertension.
EPO 590272 B 1 describes 17-aryl and 17-heterocyclyl-5-β, 14-β-androstane derivatives and their use for the treatment of cardiovascular disorders such as heart failure and hypertension.
WO2008148812 describes 17-β-(3-furyl) and (4-pyridazinyl)-5-beta, 14-beta-androstane derivatives and their use for treatment of restenosis after angioplastic or endoartherectomy, and diseases due to organ fibrosis.
None of the publications above mentioned disclose the use of the 5beta, 14beta-androstane derivatives for the prevention and/or treatment of proteinuria, glomerulosclerosis and renal failure.
It has now been found that 17-β-(3-furyl) and (4-pyridazinyl)-5-β, 14-β-androstane derivatives according to the present invention are useful agents for the prevention and treatment of proteinuria, glomerosclerosys and renal failure.